Solid-Phase Synthesis and Combinatorial Technologies

584 MATERIALS AND POLYMERIC COMBINATORIAL LIBRARIES

a library discrete with an empty space of 420 m between each position to isolate the library elements. The thin films were deposited with an electron gun using solid, ultrapure pellets of the library components. At first four columns were produced (step a, Fig. 11.3) using a moving mask M1 with a 19.1-mm-wide rectangular slit (one-quar- ter of the wafer width) and depositing, from left to right, SnO2 (480 nm thickness), V (160 nm), Al2O3/V (150 + 80 nm), and Al2O3 (300 nm). This was followed by deposition of four rows using the same mask after a 90° rotation (step b), giving thin films of varying thicknesses, from top to bottom, of La2O3 (100 to 400 nm), Y2O3 (from 100 to 400 nm), MgO (from 400 to 100 nm), and SrCO3 (from 400 to 100 nm). Each of the 16 subregions was then treated with thin films of activators using a moving mask M2 with four 4.8-mm rectangular slits (one-sixteenth of the wafer width) to deposit layers of varying thicknesses (step c), from top to bottom, of Eu2O3 (from 0 to 53 nm), Tb4O7 (from 0 to 26 nm), Tm2O3 (from 0 to 24 nm), and CeO2 (from 0 to 25 nm). Deposition was followed by slow heating to homogenize the deposited layers and to create the library individuals. L2 was first heated to 500 °C using a 4 °C/min differential and maintained at 500 °C for 2 h (step d); then it was further heated to 850 °C using the same differential and kept at 850 °C for 5 h (step e) before cooling to 100 °C with a 10 °C/min differential (step f, Fig. 11.3). More than 2500 components showed red, green, or blue emission properties when excited at 254 nm with ultraviolet lamps. Some of the most active library individuals are reported in Table 11.1 on the basis of their chromaticity index (CIE, Table 11.1).

Red phosphors were the most active and numerous (>1700) library individuals found, with intensities comparable to known, commercially available luminescent materials. Their composition (Y, V, Al, and La with Eu as an activator) inspired the design of a focused library L3 (Fig. 11.4), made by deposition of films of Eu2O3 (26.3 nm) and V (189.6 nm) on a triangular silicon wafer (step a), followed by the deposition

TABLE 11.1 Red, Green, and Blue Phosphors from L2

aRelative luminosity ranking/population of the phosphor class. bR = red, G = green, B = blue.

cCommercial standards: red, Y1.9O2SEu0.1, x = 0.629, y = 0.35; green, ZnS–Cu, Al, x = 0.266, y = 0.576; blue: ZnS–Ag, Cl, x = 0.15, y = 0.05.

Y0.82Al0.07La0.06Eu0.05VO4

11.1

Figure 11.4 Structure of the photoluminescent materials discrete library L3 and of the most active library individuals 11.1 and 11.2 from its screening.

ofgradientsofY2O3,Al2O3, and La2O3 (step b, from 0 to 100%, Fig. 11.4). The composite 11.1 produced the maximum intensity as a red phosphor and was further optimized to the final compound 11.2 by variation of the activator concentration (Fig. 11.4).

Compound 11.2 was then prepared in large quantity and was fully characterized, showing similar if not better efficiency properties when compared with the commercial standard 11.3 (Fig. 11.4). Moreover, the quantities of both expensive elements Y and Eu were reduced in 11.2, while V provided an increase of red chromaticity. A simple primary/focused library scheme thus allowed the identification of novel blue and green phosphor composites and the optimization of the properties and the reduction of the cost of efficient red phosphors.

The same library was used by the authors to identify a novel, blue-white emission composite identified as Sr2CeO4 (39, 40). Another prominent group identified magnetoresistant materials (41) and novel capacitors (42) from smaller discrete materials libraries, while joint efforts by a multi-lab group (43) proved the applicability of combinatorial technologies to the development of molecular plastic solar cells. Further examples will be described in the next section with greater focus on screening procedures.

More sophisticated and miniaturized liquid dispensing units, based on the inkjet technology (Section 6.4.1), were used by Sun et al. (45) to prepare a 100-member microscale discrete photoluminescent library L5 made of 50 ternary (La, Al, Eu or Gd, Al, Eu) and 50 quaternary composites (La, Gd, Al, Eu; Fig. 11.6). The library was made in around 30 min on a scale of 0.1 mg of composite per well. The starting reagents were added as droplets from standard 0.5 M water/ethylene glycol solutions for La, Gd, and Al and a 0.1 M solution for Eu. The one hundred 1-mm-deep, 1-mm-diameter ceramic wells were treated, after evaporation of the solvents, at 900 °C for 1 h, and the phosphor activity was measured as reported in Section 11.1.3. A promising red phosphor 11.6, with defined composition, was identified and structurally characterized (Fig. 11.6). The use of a sophisticated but “handmade” inkjet delivery system allowed the miniaturization of volumes and quantities, the automation of the process, and its high reliability (<2% fluctuation in the dimensions and contents of each droplet). The forecasted scalability of up to thousands of library individuals makes this system extremely appealing for other applications.

Some interesting devices, both on classical (46) and miniaturized scale (47, 48) have been developed for the combinatorial hydrothermal synthesis of zeolites (49, 50). Solutions of suitable precursors were dispensed into the wells of the multireactor autoclaves, which were then sealed and heated following appropriate protocols. X-ray characterization of the individuals allowed the determination of the properties of the library individuals. Both protocols and instruments allowed the synthesis of hundreds of composites and their automated (47) or semiautomated (46, 48) work-up and characterization. Structural information was derived from both reports, proving the applicability of combinatorial technologies to hydrothermal synthesis procedures.

This and many other fields, using both solid-state and solution-phase synthetic procedures, are expected to benefit significantly from the use of combinatorial technologies. Unprecedented applications will surely appear due to the increasing popularity of materials science applications in the combinatorial chemistry scientific arena.

L5

Figure 11.6 Structure of the photoluminescent materials discrete library L5 and the most active library individual 11.6 from its screening.

588 MATERIALS AND POLYMERIC COMBINATORIAL LIBRARIES

11.2 CHARACTERIZATION AND SCREENING OF MATERIALS SCIENCE LIBRARIES

11.2.1 General Considerations

Combinatorial technologies in pharmaceutical research have received a boost from the need to access chemical diversity with a similar throughput in respect to the available biological screening techniques, which can determine the activity of large libraries in short periods of time. High-throughput analytical techniques for the characterization of organic library individuals are also available, allowing reliable and fast quality control procedures. Even though the very first “combinatorial” report dealt with materials science (19), the scarce portfolio of high-throughput screening methods for composites has failed to stimulate the expansion of combinatorial materials science. The long and labor-intensive characterization process for novel composites has also contributed to prevent the growth of combinatorial applications in materials science.

The above-mentioned synthetic methods, either in solution or as solid-state protocols, have put additional pressure on the fast characterization and screening of materials libraries. The latter subject has been approached by various groups, and several high-technology methods have been reported. They will be briefly presented and discussed via several examples in this section. As of today, structural characterization of library individuals is still troublesome, nongeneralizable, and time consuming. Moreover, it has often proven to be essential to evaluate the quality of a library, and thus this process cannot be avoided. The tendency is to fully characterize a few library members and to assume that their composition and adherence to the planned composite in that library portion are indicative of the whole library purity and quality.

As a comment, solid-state thin-film deposition has significantly improved the throughput and the quality of prepared materials, but the resynthesis of active individuals in large quantities is often performed with more classical solid-state methods. The actual identity of the composition of the “combinatorial” and the “classical” material must be carefully controlled, because even small diffusion resistances during the nucleation/crystallization phases may produce highly different products with significant activity variations, leading to both false positives and negatives.

11.2.2 Screening Libraries for Heterogeneous Catalysts

Several libraries of heterogeneous catalysts have been screened using IR thermographic imaging (51), resonance-enhanced multiphoton ionization (52), and mass spectrometry (53), among others. Example of these screening methods are given below.

Holzwarth et al. (51) reported the synthesis and IR thermographic-imaging screening of a 37-member, focused discrete heterogeneous catalyst library L6 for oxidations and reductions. The library was prepared using sol–gel solution synthetic protocols (47, 51) to produce the library individuals as amorphous microporous mixed oxides (AMMs), which have previously shown heterogeneous catalytic properties (54, 55). The scaffolding metal oxides contained either Ti (subset 1, Fig. 11.7) or Si (subset 2), and many active metal components were used. The complete structure of L6 is reported

Figure 11.7 Structure of the amorphous microporous mixed (AMMs) oxides discrete catalytic library L6.

in Fig. 11.7 (Mn3Ti signifies 3 mol % of manganese in 97% titania sol, and the same representation is used for the other library individuals). The Tior Si-based sols were prepared with the appropriate metal composition and added to the appropriate well of an inert reaction block (a few microliters per well, amounting to <200 g). The sols were then concentrated, progressive heating was applied, and final reduction of the metal salts produced the AMM active library L6.

The library was tested as a source of heterogeneous catalysts for three processes: the reduction of 1-hexyne and the oxidation of iso-octane or toluene. IR thermographic imaging (56), a technique already applied to bead-based libraries (57) and to heterogeneous catalysis (58), was employed to screen L6. The reaction block was first heated to the desired temperature; then the appropriate reagent was passed over the block together with a stream of hydrogen (reduction) or air (oxidation). IR thermal images were taken with a steady flow of reagents and were used to discriminate catalytic efficiencies. The temperature of each library individual should only have been increased if catalytic activity was releasing a heat of reaction at its surface. The IR image of the library could be directly related to the temperature of each potential catalyst after adjusting the image of each well for its different composition by subtraction of a blank, that is, the heated reaction block in the absence of the reactants. The three reactions were analyzed, and the results clearly showed different SARs between all three reactions. For example, Pd1Ti was extremely active for iso-octane oxidation but was inactive toward toluene oxidation, while Pt5Ti showed the opposite behavior. Small differences could easily be spotted, even with <1 °C temperature differences and small quantities of catalysts, confirming the sensitivity and the reliability of the screening method.

Senkan and Ozturk (52) reported the synthesis and screening of a 66-member discrete heterogeneous catalyst library L7, containing Pt, Pd, and In, for the dehydrogenation of cyclohexane to benzene at 300 °C. The structure of L7 and its synthesis are reported in Fig. 11.8. Sixty-six porous alumina pellets (30 mg each) were shaped into 0.3-cm-diameter, 0.1-cm-high cylinders (step a), then immersed in aqueous HCl solutions containing the 66 appropriate mixtures of InCl2, PdCl2, and H2PtCl6 (step

590 MATERIALS AND POLYMERIC COMBINATORIAL LIBRARIES

(PtxPdxInx) alumina

L7

66-member discrete library

x = 0.1 increments from 0 to 1%

a:shaping of alumina pellets; b: treatment with aq. HCl solutions of H2PtCl6, PdCl2 and InCl2;

c:incubation at rt for 24 hrs; d: solvent evaporation; e: drying at 90°C (4 hrs) and 120°C (4 hrs); f: calcination at 500°C (2 hrs); g: placement of the cylinders in the reaction block;

h:heating at 350°C under helium; i: reduction with hydrogen (2 hrs).

Figure 11.8 Structure and synthesis of the sol–gel discrete library L7.

b). Adsorption was continued at rt for 24 h (step c); then the solvent was evaporated and the homogeneous metal–alumina pellets were dried (steps d and e). The library was calcinated for 2 h at 500 °C (step f) to give an average metal content and a total Cl– content of around 1% in each library individual. The library was then placed in a particular microreactor that ensured the isolation of each pellet/library individual, the uniform exposure of the library to the same flow of reactants, and the uniform heating of the whole microreactor (step g). After heating to 350 °C under helium (step h), the gas source was switched to hydrogen for 2 h to reduce the metal cations to active metals, producing L7 (step i, Fig. 11.8).

The screening protocol for catalytic activity consisted of lowering the temperature to 300 °C under helium (step a, Fig. 11.9), then introducing 10% cyclohexane in helium carrier gas to the microreactor (step b). Benzene formation was detected using resonance-enhanced multiphoton ionization (REMPI; 59, 60), a technique that detects molecules via their excitation when they are hit by a first photon (equation 1, Fig. 11.9), and their ionization caused by a second photon (equation 2, Fig. 11.9). The photons were generated by a suitable laser source tuned to 259.7 nm, a specific wavelength where benzene is excited and ionized while cyclohexane, argon, and hydrogen are not affected. The laser source was applied to a window in the microreactor allowing irradiation of the gas stream (step c), and a pair of moving microelectrodes were used to detect the relative amount of benzene-derived cations formed in the vicinity of each library pellet (step d, Fig. 11.9). The whole cycle was repeated five times as the microreactor could only host 17 separate reactions at once. The screening results showed how Pt and Pd were generally good catalysts, while In was inactive as

a: hydrogen removal under helium at 300°C; b: introduction of 10% cyclohexane gaseous reaction stream; c: laser source, ionization of benzene; d: REMPI quantitative determination.

BEST COMPOSITION:

(Pt0.8Pd0.1In0.1) alumina

11.7

Figure 11.9 Screening of the sol–gel discrete catalytic library L7 with REMPI and structure of the most active catalyst 11.7 for the oxidation of cyclohexane.

expected. An a priori unpredictable ternary composition 11.7 (Fig. 11.9) was found to be the best catalytic library composite.

Cong et al. (53) reported the synthesis and screening of the 120-member discrete materials library L8 as a source of heterogeneous catalysts for the oxidation of CO to CO2, promoted either by O2 (equation 1, Fig. 11.10) or by NO (equation 2, Fig. 11.10). The library were prepared on a circular, 7.5-cm-diameter quartz wafer using a triangular architecture. A 15 × 15 × 15 grid of Rh–Pd–Pt alloys was obtained by radiofrequency sputtering of the metals onto the substrate, using moving masks to obtain the desired composition for each library individual, and the desired metal gradient from an apex of the triangle (100% pure metal) to the facing side (0% of the same metal, binary mixtures of the other library components, Fig. 11.10). Ten deposition steps, each producing a thin metal film of around 10 nm, yielded an average of 2–4 µg of metal alloy with a thickness of around 100 nm for each library individual. The quality of the library and the complete intermetal mixing of the layers was confirmed by X-ray analysis.

The quartz substrate holding the library was then transferred to the screening apparatus, which is schematically depicted in Fig. 11.11 (61). A CO2-heating laser was focused on a specific library individual, heating it to the desired temperature (300, 350, or 400 °C for O2-promoted CO oxidation; 400, 500, or 600 °C for NO-promoted CO oxidation) without affecting the neighboring library individuals. Subsequently, a gas stream containing the appropriate reagents was delivered to the heated catalyst through a miniaturized system, with occasional sampling and delivery of the reaction gases to a mass detector to determine the quantity of the reaction products via the measured